RTP On Demand: Current and Future Role of PARP Inhibitors in the Management of Ovarian Cancer (Video Program) - Video 10Niraparib maintenance therapy for platinum-sensitive, recurrent OC
7:44 minutes.
TRANSCRIPTION:
DR HERZOG: This is a Phase III, double-blinded randomized trial in which they were looking at niraparib versus placebo, in those who were platinum sensitive, used as maintenance therapy. DR LOVE: So they got a platinum-containing chemotherapy first. DR HERZOG: Correct. DR LOVE: And then this maintenance. What kinds of chemotherapy did they receive? DR HERZOG: Most of them received platinum-based chemo. DR LOVE: So they got maintenance therapy after chemotherapy. How long was the maintenance therapy given? And how was the trial actually structured in terms of who went into it? DR HERZOG: Well, they received maintenance until either disease progression or toxicity. DR LOVE: So it was basically indefinite. And what was observed there in terms — particularly in terms of progression-free survival that they reported? DR HERZOG: Well, it depends on which group you look at. There were several groups. Overall, there were 553 patients that were enrolled in this trial. If you look at the germline-negative group that had tumor mutation, there was a difference of 9.9 months in treatment with niraparib versus placebo: 20.9 versus 11 months, highly statistically significant. Then you look at the germline-negative, HRD-positive but BRCA wild-type: There was a 5.6-month difference, 9.3 versus 3.7 months, highly significant as well. And then a little less difference for those that were germline-negative and did not have HRD. There was a 3.1-month difference there. But if you look overall at the study — a very impressive hazard ratio. You’re looking at, for those that were non-germline mutated, you’re looking at 9.3 versus 3.9. I think I already said that. DR LOVE: I guess the one thing that really strikes out is, first of all, the patients with the germline BRCA mutations, the hazard ratio was 0.27, so a 73% reduction in progression. Then you look at the nongermline, but who had HRD positivity: Hazard ratio 0.38, 62%, still really impressive. But the thing that really struck me was, as you said, the patients who did not have germline BRCA mutations and also didn’t have HRD positivity, they still had a hazard ratio of 0.45, a 55% reduction in recurrence. I mean, you tell me. Has that been reported in any trial of a PARP inhibitor previously? DR HERZOG: Well, not to those numbers. So if you break down some of the other data from the olaparib data, there do appear to be some patients that benefited, that were in that class. But they didn’t have those types of numbers in terms of size, that you could really look at the magnitude of effect and feel confident in those. I mean, you’re looking at a fairly large number of patients. And I think that’s important to point out because you’re looking at — in this, you had 350 out of the 553 that were non-germline BRCA mutated. One hundred, sixty two of those were considered to have homologous recombination deficiency, of which 47 had somatic BRCA and 115 were wild type. And you saw significant activity with those, as well as those, as you pointed out, of 134 patients that were homologous recombination deficiency-negative and non-germline mutated. So I think that that’s really the important part of this study. To your point is that we’re seeing significant activity. If you compared that to a chemotherapeutic drug, you would be extremely excited with those results. So I think that that’s something that is really worth taking note of and will be something that’ll be very interesting, right, when you take this to the regulatory authorities, as to what the label will read. DR LOVE: Right. Well, certainly what’s seen in this situation, which is basically platinum-sensitive recurrence. I guess we don’t have survival data yet. It’s not mature enough for survival? Is that your understanding? DR HERZOG: Correct. DR LOVE: But yes, just based on these curves, that you would think it would be something people would want to utilize. If this drug were available right now, would you utilize it in this situation? And would you consider utilizing olaparib, if you could access it, in this situation, even though it’s not indicated? DR HERZOG: Yes. I mean, I think we’d have to see what the label reads on niraparib, and certainly, I think, for olaparib we’ll be seeing more data coming out in this particular setting as well. And so that data should be coming out in the next year or so. DR LOVE: Also the issue in terms of tolerability in this study, you mentioned thrombocytopenia. And they report 61% with the niraparib group versus 5.6% in placebo. To what extent do you see bleeding? Do you have to use platelet transfusion? Is this more a lab finding? DR HERZOG: Yes. By and large, it is that. In terms of Grade 3/4, though, I think that there was a fair amount of thrombocytopenia. And I think it was 34%? DR LOVE: So Grade 3/4 thrombocytopenia was just about 34% versus almost none in the placebo group, so significant. DR HERZOG: It is. DR LOVE: So if the drug were available, you could access it, how would you utilize it right now? DR HERZOG: I think the setting that they’ve utilized it in, in this study, is perfect. This is something that would be very appealing. It’s an oral agent, which makes it appealing for a maintenance therapy in the sense that you don’t have to have somebody come into the office to receive therapy. DR LOVE: What about in platinum-resistant disease? Would you want to give it, or do you need to see a trial? DR HERZOG: I’d like to see more data in that. Certainly, if you look at the olaparib data, the current — the Kaufman paper that led to approval here in the US included patients that had platinum-resistant disease. So some were platinum sensitive, but many were platinum resistant. DR LOVE: So of course I’m sure this is going to be looked at in trials. And you can talk about it, but what about the issue of using it up front after initial chemotherapy after debulking surgery, for example? DR HERZOG: One of the big questions — and I think this is certainly where we’re going with our discussion here — is, where do we best position these active agents? And ideally, you put your best agents forward, so that you can, in fact, produce the most number of cures. And so that’s really the hope, is that if you move this up you might actually be able to cure more women with ovarian cancer. Now, having said that, we don’t have any data to support that hypothesis, but it’s certainly a hypothesis well worth testing. The only caveat would be if you’re using this on patients who are potentially cured — do recall that over 20% of our advanced-stage ovarian cancers are survivors for well over 5 years and beyond, in some cases cured — we have to be mindful then of the potential long-term complications of these drugs. And then how long do they need to stay on them and so forth? And we don’t have any of that worked out at this point. But there are trials out there right now looking at PARP that’s been moved up to front line. |